1. Field of Invention
This invention relates to methods for reducing inflammation, inhibiting fibrosis, scarring, fibroblast proliferation, post-operative infection while also promoting smooth gliding of the tendon and healing using processed amnion and/or chorion tissues as part of a surgical intervention treatment program to repair damaged or diseased tendons.
2. Background of the Invention
Tendons are a type of regularly arranged dense soft, connective tissue that bridges and attaches muscles to bone. This fibrous and flexible tissue is also called sinew. Tendons are comprised of type I collagen (80% by weight) that are arranged in fibrils. The fibrils form a fascicle, which includes the basic tendon fibril and also fibroblasts in parallel rows. Covering the tendon is a thin fascia tissue membrane. Tendons also contain some elastin fibers, a proteoglycan matrix and proteinaceous filler between the connective tissue fibers.
When tendons are ruptured due to trauma or surgical intervention, they typically take longer than, for example, bone to heal. Tendons have poor spontaneous regenerative capabilities and complete regeneration is almost never achieved despite intensive remodeling. One of the reasons for this is the absence of tendon sheathing. Tendons have a thin fascia membrane cover which protects the tendon while also allowing it to move and slide freely against adjacent tissue structures like muscle, skin or bone.
Patients whose tendon(s) have been ruptured experience pain, reduced mobility, reduced lubrication between the articulating and adjacent tissues and a heightened risk of post trauma scarring, adhesions and pain. A primary cause of this is damage to the protective sheathing of the tendon.
When a tendon sheath is injured, stressed or traumatized, the natural response of the damaged tissue is to increase the tensional forces thus making a “sling” over the injured tendon. The tendon sheath also responds to trauma by “gluing” affected areas of the site of tendon injury. After the tendon trauma, the fascia sheathing sometimes “forgets” to unglue and patients then experience a layer of tendon and adhesion to the tendon injury site. In those cases, the tendon no longer slides and adjacent structures painfully tether and tug at each other.
A classic example of this phenomenon is called “trigger finger”. In this case the tendon fascia sheath has narrowed and begun to “glue” onto the finger tendon. The membrane then becomes inflamed (tenosynovitis). That inflammation then causes the tendon to swell, which constricts further the ability of the tendon to glide between adjacent structures and the tendon no longer moves smoothly through its sheath. In the case of “trigger finger” the finger locks into an upward position.
In other cases, during the healing process following a traumatically injured tendon, the body may deposit an excess amount of fibrous collagen at the site of injury. Physicians refer to this excess proliferation of fibrous collagen as surgical adhesions or scar tissue formation at the site of injury.
The surgical option offers a significantly smaller risk of re-rupture compared to traditional non-operative management, e.g., 5% vs 15% for treatment of acute Achilles tendon ruptures. See Richter J et al., Zentralbl Chir, 1994, 119 (8):538-44. However surgery imposes much higher relative risks of perioperative mortality and morbidity, e.g. infection including MRSA, bleeding, deep vein thrombosis, lingering anesthesia effects, stiffness, suture reaction, persistent pain or weakness after the injury and repair, etc.
Peritendonous adhesions are a contributor to poor outcomes in patients undergoing tendon surgery. Following tendon repair surgery, fibroblasts from surrounding tissues migrate into the wound during the healing process leading to the formation of scar tissue. Peacock E K. In: Peacock E K (ed) Wound repair. W B Saunders, Philadelphia, 1984; pp 263-331. The formation of adhesions between the tendon and surrounding tissue reduces the ability of the repaired tendon to glide normally. This limits post-operative rehabilitation as a result of a reduction in range of motion and an increase in inflammatory pain.
A product which would effectively inhibit fibroblast formation, scarring and adhesion formation can be useful for treating ruptured and otherwise injured tendons.
Current measures for treating excess scarring and adhesions on traumatized tendons include bovine collagen wraps, sheets of hyaluronic acid and hydroscopic polymers (for example; polyethylene glycol) based barriers. In published clinical studies, none of these approaches have shown to consistently reduce the incidence of adhesions or scar formation following repair of tendon injury.
The amnion is a thin, cellular, extra-embryonic membrane that forms the inner membrane of a closed sac surrounding and protecting an embryo in reptiles, birds, and mammals. The sac contains the fetus and amniotic fluid or liquor amnii, in which the embryo is immersed, nourished and protected. Typically, the amnion is a tough, transparent, nerve-free, and nonvascular membrane consisting of two layers of cells: an inner, single-cell-thick layer of ectodermal epithelium and an outer covering of mesodermal, connective, and specialized smooth muscular tissue. In the later stages of pregnancy, the amnion expands to come in contact with the inner wall of the chorion creating the appearance of a thin wall of the sac extending from the margin of the placenta. The amnion and chorion are closely applied, though not fused, to one another and to the wall of the uterus. Thus, at the later stage of gestation, the fetal membranes are composed of two principal layers: the outer chorion that is in contact with maternal cells and the inner amnion that is bathed by amniotic fluid.
The amnion has multiple functions, i.e., as a covering epithelium, as an active secretary epithelium, and for intense intercellular and transcellular transport. Before or during labor, the sac breaks and the fluid drains out. Typically, the remnants of the sac membranes are observed as the white fringe lining the inner cavity of the placenta expelled after birth. The amnion can be stripped off from the placenta. The amnion has a basement membrane side and a stroma side. The fetal membrane including amnion and chorion has been used in surgeries documented as early as 1910. See Trelford et al., 1979, Am J Obstet Gynecol, 134:833-845. Amnioplastin, an isolated and chemically processed amniotic membrane, was used for continual dural repair, peripheral nerve injuries, conjunctival graft and flexor and tendon repair. See e.g., Chao et al., 1940, The British Medical Journal, March 30. The amnion has been used for multiple medical purposes, e.g., as a graft in surgical reconstruction forming artificial vaginas or over the surgical defect of total glossectomy, as a dressing for burns, on full-thickness skin wounds or in omphalocele, and in the prevention of meningo-cerebral adhesions following head injury or tissue adhesion in abdominal and pelvic surgery.
In 1962, the fetal membrane was used to treat pelvic basins after total exenteration in dogs, however, trials in human proved disappointing.
In recent years, there have been renewed interests in the application of amnion in ocular surface reconstruction, for example, as an allograph for repairing corneal defects. See, for example, Tsai and Tseng, Cornea. 1994 September; 13(5):389-400; and Dua et al., Br. J. Ophthalmol 1999, 83:748-20 752. In addition, amnion and amniotic fluid have recently been used as sources of placental stem cells. See, e.g., U.S. Pat. No. 7,255,879 and WO 200073421.
The role of the amniotic membrane was investigated in chickens with regard to the prevention of adhesion formation following tendon repair in zone II. Results of histologic examination demonstrated that use of the amniotic membrane significantly reduced the amount of adhesion compared with the other groups. Three months after implantation no remnants of amniotic membrane could be identified at the tendon repair site. Demirkan et al., Archives of Orthopaedic and Trauma Surgery, 2002, 122:396-399.
Despite the clinical and published record regarding the safety and efficacy of amnion in broad surgical use, issues regarding reproducibility, safety and the precise form of amnion for each prospective indication have prevented amnion from achieving broad commercial distribution.
There is a need of improved methods and products that would effectively inhibit fibroblast formation, scarring and adhesion formation in treating ruptured and otherwise injured tendons. The present invention relates to such improved methods and products.